Myeloproliferative disorders in humans are a major health problem.
Myeloproliferative disorders are characterized as a group of diseases related to abnormal proliferation of blood cells produced in bone marrow.
Myeloproliferative disorders include Philadelphia chromosome positive and Philadelphia chromosome negative categories. Clinically, Philadelphia chromosome positive myeloproliferative disorder typically is manifested as chronic myelogenous leukemia whereas the major Philadelphia chromosome negative myeloproliferative disorders are essential thrombocythemia, polycythemia vera, and myelofibrosis. Often these myeloproliferative disorders evolve in cancer e.g., leukemia.
Myelofibrosis and essential thrombocythemia are associated with JAK2 mutation or thrombopoietin receptor mutation and are characterized as having two different phases: the cellular phase having increased megakaryocytes which cluster, reticulin fibrosis, later trichrome (collagenous) fibrosis, and increased myeloid precursors and the fibrotic phase having collagenous fibrosis with lack of marrow elements.
Polycythemia vera is associated most often with JAK2 mutation and is also characterized as having two phases similar to those in myelofibrosis.
The definitions of these diseases are still evolving based on genetic mutation and disease history etiology.
The discovery of the JAK2 V617F mutation in 2005 provided some evidence to suggest a common pathogenesis for the Philadelphia Chromosome negative myeloproliferative disorders (Campbell et al. (2005) Lancet December 3; 366(9501):1945-53).
A group of enzymes known as lysine methyl transferases and lysine demethylases are involved in histone lysine modifications. One particular human lysine demethylase enzyme called Lysine Specific Demethylase-1 (LSD1) was recently discovered (Shi et al. (2004) Cell 119:941) and shown to be involved in histone lysine methylation. LSD1 has a fair degree of structural similarity, and amino acid identity/homology to polyamine oxidases and monoamine oxidases, all of which (i.e., MAO-A, MAO-B and LSD1) are flavin dependent amine oxidases which catalyze the oxidation of nitrogen-hydrogen bonds and/or nitrogen-carbon bonds. Although the main target of LSD1 appears to be mono- and di-methylated histone lysines, specifically H3K4 and H3K9, there is evidence in the literature that LSD1 can demethylate methylated lysines on non-histone proteins like p53, E2F1, Dnmt1 and STAT3.
Several groups have reported LSD1 inhibitors in the literature. Sharma et al. recently reported a new series of urea and thiourea analogs based on an earlier series of polyamines which were shown to inhibit LSD1 and modulate histone methylation and gene expression in cells (J. Med. Chem. 2010 PMID: 20568780 [PubMed—as supplied by publisher]). Sharma et al. note that “To date, only a few existing compounds have been shown to inhibit LSD1.” Some efforts were made to make analogs of the histone peptide that is methylated by the enzyme; other efforts have focused on smaller molecules like molecules based on known MAO inhibitors. Gooden et al. reported trans-2-arylcyclopropylamine analogues that inhibit LSD1 with Ki values in the range of 188-566 micromolar (Gooden et al. ((2008) Bioorg. Med. Chem. Let. 18:3047-3051)). Most of these compounds were more potent against MAO-A as compared to MAO-B. Ueda et al. ((2009) J. Am. Chem Soc. 131(48):17536-17537) reported cyclopropylamine analogs selective for LSD1 over MAO-A and MAO-B that were designed based on reported X-ray crystal structures of these enzymes with a phenylcyclopropylamine-FAD adduct and a FAD-N-propargyl lysine peptide; the reported IC50 values for phenylcyclopropylamine were about 32 micromolar for LSD1 whereas compounds 1 and 2 had values of 2.5 and 1.9 micromolar respectively.
Importantly, studies have also been conducted on amine oxidase inhibitor compounds to determine selectivity for MAO-A versus MAO-B since MAO-A inhibitors can cause dangerous side-effects (see e.g., Yoshida et al. (2004) Bioorg. Med Chem. 12(10):2645-2652; Hruschka et al. (2008) Biorg Med Chem. (16):7148-7166; Folks et al. (1983) J. Clin. Psychopharmacol. (3) 249; and Youdim et al. (1983) Mod. Probl. Pharmacopsychiatry (19):63).
Currently the treatments available for myeloproliferative disorders and related diseases have serious drawbacks. There is a need for new drugs for these diseases that target novel points of intervention in the disease processes and avoid side-effects associated with certain targets.